Submissions for variant NM_000051.4(ATM):c.2466+1del

dbSNP: rs786202783

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165770	SCV000216515	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The c.2466+1delG intronic pathogenic mutation, located in intron 15 of the ATM gene, results from a deletion of the first nucleotide after coding exon 15. This alteration was reported in one patient with an additional nonsense ATM mutation in trans and a clinical diagnosis of ataxia telangiectasia (Cavalieri S, Ann. Hum. Genet. 2008 Jan; 72(Pt 1):10-8). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691683	SCV000819472	pathogenic	Ataxia-telangiectasia syndrome	2022-09-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 186216). This variant is also known as exon 17. Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 9043869, 17910737, 22927201). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 16 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872).
Sema4, Sema4	RCV000165770	SCV002532178	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-09	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000691683	SCV003800823	pathogenic	Ataxia-telangiectasia syndrome	2023-01-01	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2466+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250466 control chromosomes. c.2466+1delG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (example, PMID: 17910737, 9043869, 30389154). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003468756	SCV004212060	pathogenic	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165770	SCV004360572	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	This variant causes the deletion of G at the +1 position of intron 16 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 17910737, 22927201, 30389154). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003468756	SCV004932185	likely pathogenic	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Natera, Inc.	RCV000691683	SCV001462071	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing